Many disease states are characterized by uncontrolled proliferation and differentiation of cells. These disease states encompass a variety of cell types and maladies such as cancer, atherosclerosis, and restenosis.
The term cancer is used to describe a class of diseases characterized principally by uncontrolled cell growth. Cancer is currently one of the leading causes of death in the world, and is projected to become the leading cause of death in the next few years. By 2030, it is projected that there will be more than 20 million new cancer diagnoses per annum, with at least 13 million deaths.
There are many different forms of cancer, and many of these types require different forms of treatment. The current main forms of treatment for cancer include surgery, radiation therapy, bone marrow transplantation, immunotherapy, anti-angiogenic therapy, and treatment with cytotoxic agents (commonly known as chemotherapy). A large number of cytotoxic agents have been used for the treatment of cancer over the last 70 years, including nitrogen mustards such as chloromethine and estramustine; anthracyclines such as doxorubicin, daunorubicin, and idarubicin; platinum-containing compounds such as cisplatin, carboplatin and oxaliplatin; antimetabolites such as dacarbazine, capecitabine, fludarabine, 5-fluorouracil, gemcitabine, methotrexate, and pemetrexed; topoisomerase inhibitors such as topotecan and irinotecan; inhibitors of tubulin polymerization such as vinblastine and vincristrine; and inhibitors of tubulin depolymerization such as paclitaxel and docetaxel.
Although many anti-cancer agents are known and have achieved considerable success as therapeutic agents for the treatment of a variety of cancers, there is still a significant unmet need for new therapies for cancer.
Eukaryotic initiation factor 4E (eIF4E) is a 24 kDa protein that plays a key role in the initiation of translation of mRNA. At the initiation of mRNA translation, eIF4E binds to the 7-methylguanosine cap at the 5′ end of mRNAs, and forms a complex (called eIF4F) with the scaffolding protein eIF4G and the helicase eIF4A. The formation of this complex is required for the initiation of cap-dependent translation and therefore the binding of eIF4E to eIF4G is a critical event in this process.
eIF4E has been identified as a promising target in the field of oncology because of a number of pieces of data that implicate it in transformation and tumorigenesis.
Two small molecule inhibitors of the eIF4E-eIF4G interaction have been disclosed by Gerhard Wagner and colleagues (Moerke, N. J. et al. Cell 2007, 128, 257-267). These inhibitors have the formulae i and ii. Rigidified analogues of the compound of formula ii were disclosed by the Wagner group at the 240th National Meeting of the American Chemical Society (Aug. 22-26, 2010) (see MEDI-28, MEDI-78, MEDI-94, and MEDI-479, which have been abstracted in Chemical Abstracts as AN 2010:1011638, AN 2010:1011687, AN 2010:1011703, AN 2010:1012083, respectively). The activity of the compound of formula ii has been demonstrated in vivo in a rat model of fear consolidation, which depends on the formation of the eIF4F complex (Hoeffer, C. A. et al. Proc. Nat. Acad. Sci. USA 2011, 108, 3383-3388). In another study, the compound of formula ii, when combined with the apoptosis-inducing protein TRAIL, inhibited the eIF4E/eIF4G interaction and also inhibited the growth and induced apoptosis in human lung cancer cells. However, further experiments using siRNA suggest that the augmentation of TRAIL activity by 4EGI-1 is independent of cap-dependent translation (Fan, S. et al. Neoplasia 2010, 12, 346-356).
